Never-smokers with lung cancer had significantly higher plasma levels of 37 environmental compounds, including trifluoroacetic acid and pesticides, compared to smokers (P < 0.05).
Do chemical exposome profiles differ between never and ever smokers with non-small cell lung cancer, and do they correlate with mutational signatures?
Never smokers with non-small cell lung cancer exhibit distinct chemical exposome profiles compared to smokers, with higher levels of certain environmental exposures that correlate with specific mutational signatures.
Absolute Event Rate: 0% vs 0%
Abstract Non-small cell lung cancer in never smokers (LCINS) accounts for ∼25% of all cases and is the fifth highest cause of cancer death. LCINS disproportionately affects women and has been reported to be associated with environmental exposures, such as air pollution and radon. Prior LCINS studies investigating environmental risk factors often relied on geospatial estimates of exposures rather than individual-level exposures. In addition, information on the relationship between these exposures and tumor characteristics, such as mutational signatures (MutSigs), is limited. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) profiling of plasma enables identification of chemical and metabolic exposures, i.e. the chemical exposome (CE), encountered by an individual. We conducted an exposome-wide analysis of compounds in the CE among 86 matched early-stage non-small cell lung cancer in smokers (LCIS) and LCINS cases. Whole-genome sequencing (WGS) on tumor and blood was performed on a subset of LCINS cases (N=16) to assess associations of chemical compounds and metabolites with tumor mutational burden (TMB) and MutSigs. Residential addresses were geocoded and geospatially integrated with environmental and radon data. Untargeted CE profiles were generated, and 539 annotated compounds were reproducibly detected in 75% of samples. Associations between LCIS/LCINS and CE compounds were evaluated using logistic regression; the correlation with TMB and MutSigs was assessed using Spearman’s rho. The study population consisted of 28% women; mean age was 70 years. Among the LCINS cases sequenced, most exhibited common driver mutations. After exposome-wide analysis, 37 and 9 compounds were respectively higher and lower in plasma from LCINS vs. LCIS (P 0.05). Compounds higher in LCINS included trifluoroacetic acid (TFA, a degradation product of polyfluorinated hydrocarbons), methocrifos (a pesticide), and aspartame (artificial sweetener). Among the sequenced LCINS cases, 18 single base-substitution (SBS) signatures were identified, including SBS18 (reactive oxygen species damage) in 4/16, SBS26 (defective DNA mismatch repair) in 6/16, and SBS40a in 16/16 (unknown etiology). We identified 44 compounds that were positively correlated with SBS18 (P 0.05), including the histamine precursor and inflammatory agent, histidine, and microbial metabolites. Our pilot study identified differential CE profiles between LCINS and LCIS cases, where LCINS cases showed higher exposure to environmentally relevant exposures (e.g., TFA, pesticides, food additives). Chemical and metabolic compounds were positively correlated with several MutSigs, suggesting a role in carcinogenesis potentially via relevant mechanisms such as oxidative stress and DNA repair. These findings support a role for environmental carcinogens in LCINS etiology and warrant further investigation. Citation Format: Kathryn Demanelis, Sonali Dayal, Autumn Gaither Davis, Arjun Pennathur, Riyue Bao, Jennifer Walker, Patricia Lynn Opresko, James G. Herman, Brenda B. Diergaarde, Laura P. Stabile. Environmental exposures, metabolomic profiles and mutational signatures in never and ever smokers with lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2318.
Demanelis et al. (Fri,) reported a other. Never-smokers with lung cancer had significantly higher plasma levels of 37 environmental compounds, including trifluoroacetic acid and pesticides, compared to smokers (P < 0.05).